Two Investigational Treatments for ALS Show Glimmer of Hope

The first four treatments in a platform trial for amyotrophic lateral sclerosis (ALS) failed to reach key endpoints in phase II studies, but two treatments — pridopidine and CNM-Au8 — showed glimmers of hope.

All treatments missed the primary efficacy outcome of change in disease severity from baseline through 24 weeks. The primary outcome incorporated Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total scores and survival, and was reported as disease rate ratio (DRR), with scores less than 1 indicating treatment benefit.

The studies tested pridopidine, CNM-Au8, verdiperstat, and zilucoplan (Zilbrysq) in the HEALEY ALS platform trial. Pridopidine is a sigma-1 receptor agonist, and CNM-Au8 is an aqueous suspension of gold particles. Verdiperstat is an oral myeloperoxidase inhibitor, and zilucoplan is a C5 complement inhibitor recently approved to treat myasthenia gravis.

Each study randomized three patients to a treatment group for every control, leading to approximately 120 ALS patients undergoing treatment and 160 pooled controls.

There was no significant difference between pridopidine and placebo on the primary endpoint (DRR 0.99, 95% credible interval 0.80-1.21), and the probability of DRR indicating treatment benefit was 0.55, reported Jeremy Shefner, MD, PhD, of the Barrow Neurological Institute in Phoenix, and co-authors in JAMA. No differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on secondary endpoints either, but pridopidine reached nominal significance in two of 63 exploratory endpoints and in some post hoc analyses.

The primary analysis comparing a combined CNM-Au8 dosage group versus placebo showed the DRR was 0.97 (95% credible interval 0.783-1.175) and the probability of treatment benefit was 0.65, said James Berry, MD, MPH, of Massachusetts General Hospital in Boston, and colleagues, in JAMA. Three secondary endpoints suggested no benefit or harm of CNM-Au8, but there was a suggestion of benefit in serum and plasma neurofilament light chain (NfL) measures at 24 weeks and in the survival analysis in the lower-dose CNM-Au8 group.

In the verdiperstat study, the estimated DRR was 0.98 (95% credible interval 0.77-1.24) and the probability of benefit was 0.57. Though verdiperstat was estimated to slow progression by 2% versus placebo (95% credible interval -23% to 24%), it was unlikely to alter disease progression in ALS, according to Suma Babu, MBBS, MPH, also of Mass General, and co-authors in JAMA Neurology.

The estimated DRR on the primary endpoint in the zilucoplan study was 1.08 (95% credible interval 0.87-1.31) and the probability of treatment benefit was 0.24, noted Sabrina Paganoni, MD, PhD, also of Mass General, and colleagues in JAMA Network Open. The trial was stopped early for futility.

The findings are notable because they represent the first platform trial results in ALS, observed John Turnbull, MD, PhD, of McMaster University in Hamilton, Ontario, in a JAMA editorial.

“Platform trials have the theoretical advantage over traditional randomized designs of providing a rapid and efficient structure for testing multiple potential therapeutic approaches, which has proven to be the case in other disease states, most notably and recently in COVID-19,” Turnbull wrote. “The hope is that they can provide the same efficiency and economy of scale in ALS.”

In the HEALEY ALS platform, participants completed the study after 24 weeks of undergoing treatment and could proceed to an open-label extension, Turnbull noted. Quarterly futility analysis was incorporated to eliminate interventions with minimal chance of success, and agents with encouraging results could flow smoothly to a phase III study.

By pooling placebo data across studies, the platform reduced the proportion of participants assigned to placebos to 25%, allowing more patients to receive investigational therapies. “This groundbreaking approach has been shown to reduce the time to find an effective treatment by half and decrease costs by a third or more,” said Merit Cudkowicz, MD, MSc, director of the Sean M. Healey and AMG Center for ALS at Mass General, in a statement.

Of the four regimens, two drugs — CNM-Au8 and pridopidine — are moving to phase III testing, the HEALEY ALS platform trial, researchers stated. Though neither met primary or secondary endpoints, the phase II studies showed promising trends in other measures, and helped clarify dosages and target populations for phase III studies. CNM-Au8 also has been tested in multiple sclerosis, and pridopidine has been studied in Huntington’s disease.

Zilucoplan and verdiperstat will not move to phase III trials, though deidentified placebo data and samples will be shared in public databases for future research, the researchers added. Three new studies from the platform have completed enrollment, and an additional one will launch in the future.

“These four papers and the initial few years of the platform trial have shown that when people work together, they can achieve more,” Babu said. “An answer for ALS will not come from one source, but from a larger ecosystem that unites the different pieces that are needed to bring change. There is hope, and there are people working hard to cure this complex disease in the best and most efficient way.”

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